Glimepiride aikor®
UkraineTable of Contents
INSTRUCTION |
GLIMEPIRIDE AICOREâ |
Composition:
Active substance: glimepiride:
1 tablet contains 2 mg, 3 mg, or 4 mg of glimepiride;
Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, magnesium stearate;
Coloring mixture:
tablets of 2 mg: lactose monohydrate, iron oxide yellow, tartrazine (E102), brilliant blue, sunset yellow FCF (E110);
tablets of 3 mg: lactose monohydrate, iron oxide yellow;
tablets of 4 mg: lactose monohydrate, indigo carmine.
Pharmaceutical form. Tablets.
Main physicochemical properties:
tablets of 2 mg: flat, elongated green tablets with bevelled edges, embossed with ‘G’ on one side and a groove on the other;
tablets of 3 mg: flat, elongated light-yellow tablets with bevelled edges, embossed with ‘G’ on one side and a groove on the other;
tablets of 4 mg: flat, elongated blue tablets with bevelled edges, embossed with ‘G’ on one side and a groove on the other.
Pharmacotherapeutic group.
Antiglycemic agents, excluding insulins. Sulfonamides, urea derivatives.
ATC code A10B B12.
Pharmacological Properties.
Pharmacodynamics. Glimepiride is a hypoglycemic agent active upon oral administration and belonging to the sulfonylurea group. It can be used in the treatment of type 2 diabetes mellitus.
Glimepiride acts primarily by stimulating insulin release from pancreatic beta cells.
As with other sulfonylurea agents, this effect is based on increasing the sensitivity of pancreatic cells to the physiological stimulation by glucose. In addition, glimepiride exerts a pronounced extrapancreatic effect, which is also characteristic of other sulfonylurea agents.
Insulin release. Sulfonylurea agents regulate insulin secretion by closing ATP-dependent potassium channels located in the membrane of pancreatic beta cells. Closure of the potassium channel leads to depolarization of the beta cell and, via opening of calcium channels, results in increased calcium influx into the cell, thereby triggering insulin release through exocyt游戏副本.
Glimepiride binds with high affinity to a protein in the beta-cell membrane associated with the ATP-dependent potassium channel; however, its binding site differs from the conventional sulfonylurea binding site.
Extrapancreatic activity. Extrapancreatic effects include, for example, improved insulin sensitivity of peripheral tissues and reduced hepatic insulin clearance.
Glucose utilization by peripheral tissues (muscle and adipose tissue) occurs via specific transport proteins located in the cell membrane. Glucose transport into these tissues is the rate-limiting step in glucose utilization. Glimepiride rapidly increases the number of active glucose-transporting molecules in the plasma membranes of muscle and adipose cells, thereby stimulating glucose uptake.
Glimepiride increases the activity of glycosylphosphatidylinositol-specific phospholipase C, which may correlate with drug-induced lipogenesis and glycogenesis in isolated muscle and fat cells.
Glimepiride inhibits hepatic glucose production by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn suppresses gluconeogenesis.
General characteristics. In healthy volunteers, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical stress, i.e., reduced insulin secretion, is preserved under the influence of glimepiride.
No clinically significant difference in the effect of glimepiride was observed between administration 30 minutes before or immediately before a meal. In patients with diabetes, adequate metabolic control over 24 hours was achieved with once-daily administration.
Although the hydroxylated metabolite causes a slight but statistically significant reduction in blood glucose levels in healthy volunteers, this contributes only minimally to the overall effect of the drug.
Combination with metformin. One study demonstrated improved metabolic control with combination therapy using glimepiride compared to monotherapy with metformin in patients whose diabetes was inadequately controlled with maximum doses of metformin.
Combination with insulin. Data on the use of glimepiride in combination with insulin are limited. In patients whose diabetes is inadequately controlled with maximum doses of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved a similar degree of metabolic control as insulin monotherapy; however, with combination therapy, a lower average insulin dose was required.
Special patient populations. Children, including adolescents. In a 24-week active-controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily), 285 children (aged 8–17 years) with type 2 diabetes were enrolled.
Both glimepiride and metformin led to a statistically significant reduction in HbA1c compared to baseline (glimepiride -0.95 (SD 0.41); metformin -1.39 (SD 0.40)). However, glimepiride did not demonstrate superior efficacy compared to metformin in terms of mean change in HbA1c from baseline. The difference between the two treatments was 0.44% in favor of metformin. The upper limit (1.05) of the 95% confidence interval for this difference was not below the 0.3% non-inferiority margin.
No new safety concerns were identified with glimepiride treatment in children compared to adult patients with type 2 diabetes. Data on long-term efficacy and safety in pediatric patients are lacking.
Pharmacokinetics.
Absorption. After oral administration, glimepiride has 100% bioavailability. Food intake does not significantly affect absorption but slightly slows its rate. Maximum plasma concentrations (Cmax) are reached approximately 2.5 hours after oral administration (mean value of about 0.3 μg/mL after multiple daily doses of 4 mg). A linear relationship exists between dose and Cmax, as well as between dose and AUC (area under the concentration-time curve).
Distribution. Glimepiride has a very low volume of distribution (approximately 8.8 L), roughly equivalent to the distribution volume of albumin, a high degree of plasma protein binding (>99%), and low clearance (approximately 48 mL/min).
In animals, glimepiride is excreted in breast milk. Glimepiride crosses the placenta. Penetration across the blood-brain barrier is low.
Metabolism and elimination. The mean terminal half-life at plasma concentrations corresponding to multiple dosing regimens is approximately 5 to 8 hours. A slight increase in half-life has been observed after administration of higher doses.
After a single dose of radiolabeled glimepiride, 58% of radioactivity was recovered in urine and 35% in feces. The unchanged drug was not detected in urine. Two metabolites, likely formed via hepatic metabolism (main enzyme CYP2C9), were identified in urine and feces: one hydroxy derivative and one carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3–6 hours and 5–6 hours, respectively.
Comparison of pharmacokinetics after single and multiple once-daily doses revealed no significant differences. Inter-individual variability was very low. No clinically relevant accumulation was observed.
Special patient populations. Pharmacokinetic parameters in men and women, both young and elderly patients (over 65 years), were similar. In patients with reduced creatinine clearance, a trend toward increased glimepiride clearance and decreased mean plasma concentrations was observed, likely due to enhanced elimination resulting from reduced protein binding. Renal excretion of both metabolites was impaired. Overall, no additional risk of drug accumulation is expected in these patients.
Pharmacokinetic parameters in five patients who underwent biliary tract surgery were similar to those in healthy volunteers.
Children, including adolescents. A study evaluating pharmacokinetics, safety, and tolerability after a single 1 mg dose of glimepiride administered under fed conditions in 30 children (4 aged 10–12 years and 26 aged 12–17 years) with type 2 diabetes showed that mean AUC(0-last), Cmax, and t1/2 values were similar to those observed in adults.
Preclinical safety data. Effects observed in preclinical animal studies occurred at exposure levels substantially exceeding the maximum exposure levels in humans, indicating their limited relevance to clinical practice, or were due to the pharmacodynamic action of the drug (hypoglycemia). These findings were obtained within the framework of standard safety pharmacology studies, repeated-dose toxicity studies, genotoxicity tests, carcinogenic potential, and reproductive toxicity studies. Adverse effects identified in the latter (including embryotoxicity, teratogenicity, and developmental toxicity studies) were considered consequences of the drug-induced hypoglycemic effects.
Clinical characteristics.
Indications.
Type 2 diabetes mellitus in adults when blood glucose levels cannot be controlled by diet, physical activity, and weight reduction alone.
Contraindications.
Glimpiride Aicor**®** is not indicated for the treatment of insulin-dependent diabetes mellitus type 1, diabetic ketoacidosis, or diabetic coma. The use of this drug is contraindicated in patients with severe impairment of renal or hepatic function. In cases of severe renal or hepatic dysfunction, patients should be switched to insulin therapy.
Glimpiride Aicor**®** must not be administered to patients with hypersensitivity to glimepiride or to any excipient contained in the formulation, to sulfonylurea derivatives, or to other sulfonamide drugs (risk of developing hypersensitivity reactions).
Pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").
Interaction with other medicinal products and other forms of interaction.
Concomitant administration of Glimpiride Aicor**®** with certain medicinal products may either reduce or enhance the hypoglycemic effect of glimepiride. Therefore, other medications should be taken only upon physician’s advice (or prescription). Glimepiride is metabolized via cytochrome P450 2C9 (CYP2C9). It is known that co-administration of inducers (e.g., rifampicin) or inhibitors of CYP2C9 (e.g., fluconazole) may alter this metabolism. Results from in vivo interaction studies have shown that fluconazole, one of the most potent inhibitors of CYP2C9, increases the AUC of glimepiride approximately twofold. Clinical experience with Glimpiride Aicor**®** and other sulfonylurea derivatives supports the existence of such interactions.
Potentiation of glucose-lowering effect, and thus, in some cases, hypoglycemia, may occur when glimepiride is used concomitantly with the following agents: phenylbutazone, azapropazone, and oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic agents, certain long-acting sulfonamides, metformin, tetracyclines, salicylates and p-aminosalicylic acid, MAO inhibitors, anabolic steroids and androgens, quinolone antibiotics and clarithromycin, chloramphenicol, probenecid, coumarin anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (high parenteral doses), fibrates, troglitazone, ACE inhibitors, fluconazole, fluoxetine, allopurinol, sympatholytics, cyclophosphamide, ifosfamide, and trofosfamide.
Reduced glucose-lowering effect, and consequently increased blood glucose levels, may occur when the patient is concurrently taking the following drugs: estrogens and progestogens; diuretics, thiazide diuretics; thyroid-stimulating agents, glucocorticoids; phenothiazine derivatives, chlorpromazine; epinephrine and sympathomimetics; nicotinic acid (high doses) and its derivatives; laxatives (with prolonged use); phenytoin, diazoxide; glucagon, barbiturates, and rifampicin; acetazolamide.
H2-receptor antagonists, beta-blockers, clonidine, and reserpine may either potentiate or reduce the glucose-lowering effect.
Under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine, and reserpine, the symptoms of adrenergic counter-regulation during hypoglycemia may be diminished or absent.
Alcohol consumption may unpredictably enhance or reduce the hypoglycemic effect of glimepiride.
Glimepiride may either increase or decrease the effect of coumarin derivatives.
Colesevelam binds to glimepiride and reduces its absorption from the gastrointestinal tract. No interactions were observed when glimepiride was administered at least 4 hours prior to colesevelam. Therefore, glimepiride should be taken at least 4 hours before colesevelam administration.
Special precautions for use
Glimepiride Aicur® should be taken shortly before or during a meal.
During the first weeks of treatment, there is an increased risk of hypoglycaemia; therefore, particularly careful monitoring is required.
Irregular eating patterns or skipping meals while taking Glimepiride Aicur® may lead to hypoglycaemia. Possible symptoms of hypoglycaemia include headache, intense hunger, nausea, vomiting, fatigue, apathy, drowsiness, sleep disturbances, increased motor activity, aggression, difficulty concentrating, anxiety, slowed reaction time, depressive mood, confusion, speech and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, seizures, drowsiness and loss of consciousness up to coma, shallow breathing and bradycardia. In addition, symptoms of adrenergic counter-regulation may occur, such as sweating, cold and clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris, and cardiac arrhythmias.
The clinical picture of a severe hypoglycaemic episode may resemble that of a stroke.
Symptoms of hypoglycaemia can almost always be rapidly relieved by immediate intake of carbohydrates (sugar). Artificial sweeteners are ineffective.
Based on experience with other sulphonylurea derivatives, hypoglycaemia may recur despite initial successful management.
Severe or prolonged hypoglycaemia, which is only temporarily corrected by usual amounts of sugar, requires immediate medical treatment and sometimes hospitalization.
Factors predisposing to hypoglycaemia include:
- unwillingness or (especially in elderly patients) inability of the patient to cooperate with the physician;
- inadequate food intake, irregular eating patterns, missed meals, or fasting periods;
- dietary imbalances;
- mismatch between physical exertion and carbohydrate intake;
- alcohol consumption, particularly when combined with missed meals;
- impaired renal function;
- severe hepatic dysfunction;
- overdose of Glimepiride Aicur®;
- certain decompensated endocrine disorders affecting carbohydrate metabolism or counter-regulation of hypoglycaemia (e.g. certain thyroid disorders, hypopituitarism, or adrenal insufficiency);
- concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").
Treatment with Glimepiride Aicur® requires regular monitoring of blood and urine glucose levels. Additionally, measurement of glycated haemoglobin is recommended.
Liver function and haematological parameters (particularly white blood cell and platelet counts) should be monitored regularly during treatment with Glimepiride Aicur®.
In stressful situations (such as trauma, unplanned surgery, or infections accompanied by fever), temporary transition to insulin therapy may be indicated.
Experience with the use of Glimepiride Aicur® in patients with severe hepatic dysfunction or in patients on dialysis is lacking. Patients with severe renal or hepatic impairment should be switched to insulin therapy.
Treatment with sulphonylurea drugs in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may lead to haemolytic anaemia. Since glimepiride is a sulphonylurea derivative, it should be used with caution in patients with G6PD deficiency. Alternative non-sulphonylurea agents should be considered for such patients.
Glimepiride Aicur® contains lactose monohydrate. This medicine should not be taken by patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Pregnancy. Risk associated with diabetes. Abnormal blood glucose levels during pregnancy may increase the risk of congenital malformations and perinatal mortality. Therefore, careful blood glucose monitoring in pregnant women is essential to avoid teratogenic risk.
Pregnant women with diabetes should be switched to insulin therapy. Women with diabetes should inform their physician about any planned pregnancy to allow timely adjustment of treatment and transition to insulin.
Risk associated with glimepiride. There are no data on the use of glimepiride in pregnant women. Animal studies indicate reproductive toxicity of the drug, likely related to the pharmacological action of glimepiride (hypoglycaemia).
Therefore, glimepiride must not be used at any time during pregnancy (see section "Contraindications").
If a patient taking glimepiride plans a pregnancy or becomes pregnant, she should be switched to insulin therapy as soon as possible.
Breastfeeding period.
To avoid transfer of Glimepiride Aicur® into breast milk and potential harm to the infant, this medicine should not be used by breastfeeding women. If treatment is necessary, the patient should either switch to insulin therapy or discontinue breastfeeding entirely (see section "Contraindications").
Effect on ability to drive and use machines
No studies have been conducted on the effect of this medicinal product on the ability to drive or operate machinery.
The ability to concentrate and reaction speed may be impaired due to hypoglycaemia or hyperglycaemia, or for example, due to impaired vision. This may pose risks in situations where such abilities are particularly important (e.g. driving a vehicle or operating machinery).
Patients should be warned not to allow hypoglycaemia to occur while driving. This is especially important for individuals who have difficulty recognizing early warning signs of hypoglycaemia or who experience frequent hypoglycaemic episodes. The decision to drive or operate machinery under such conditions should be carefully considered.
Method of Administration and Dosage.
Successful diabetes treatment depends on the patient adhering to an appropriate diet, regular physical activity, and consistent monitoring of blood and urine glucose levels. Failure by the patient to follow a prescribed diet cannot be compensated by taking Glimepiride Aicor® or insulin.
The dosage depends on the results of blood and urine glucose tests.
The initial dose is 1 mg (1/2 tablet of 2 mg) of glimepiride per day. If this dose achieves adequate disease control, it should be used for maintenance therapy.
If glycemic control is not optimal, the dose should be increased stepwise to 2, 3, or 4 mg of glimepiride per day, with intervals of 1–2 weeks between adjustments.
Doses exceeding 4 mg per day provide better efficacy only in individual cases. The maximum recommended dose is 6 mg of Glimepiride Aicor® per day.
If the maximum daily dose of metformin does not provide sufficient glycemic control, concomitant therapy with glimepiride may be initiated.
While maintaining the previous metformin dosage, glimepiride therapy should be initiated at a low dose, which can then be gradually increased up to the maximum daily dose, based on the desired level of metabolic control. Combination therapy must be conducted under close medical supervision.
If the maximum daily dose of Glimepiride Aicor® does not provide adequate glycemic control, concomitant insulin therapy may be initiated when necessary. While maintaining the previous glimepiride dosage, insulin therapy should be started at a low dose, which can then be increased based on the desired level of metabolic control.
Combination therapy must be conducted under close medical supervision.
Typically, a single daily dose of glimepiride is sufficient. It is recommended to take the dose shortly before or during a substantial breakfast, or—if breakfast is not taken—shortly before or during the first main meal of the day. Errors in drug administration, such as missing a scheduled dose, should never be corrected by taking a higher dose at the next administration. The tablet should be swallowed whole, without chewing, with liquid.
If a hypoglycemic reaction occurs in a patient taking 1 mg of glimepiride per day, this indicates that diabetes may be controlled by diet alone.
Improved diabetes control is often accompanied by increased insulin sensitivity; therefore, during treatment, the need for glimepiride may decrease. To avoid hypoglycemia, the dose should be gradually reduced or therapy discontinued altogether. Re-evaluation of dosage may also be necessary if the patient experiences changes in body weight or lifestyle, or if other factors affecting the risk of hypo- or hyperglycemia arise.
Switching from Oral Hypoglycemic Agents to Glimepiride Aicor®.
Transition from other oral hypoglycemic agents to Glimepiride Aicor® is generally possible. When switching, the potency and half-life of the previous agent should be considered. In some cases, especially when the previous antidiabetic agent has a long half-life (e.g., chlorpropamide), it is recommended to wait several days before initiating Glimepiride Aicor® to reduce the risk of hypoglycemic reactions due to additive effects of the two agents.
The recommended initial dose is 1 mg of glimepiride per day. As noted above, the dose may be gradually increased based on the patient's response to the drug.
Switching from Insulin to Glimepiride Aicor®.
In exceptional cases, patients with type 2 diabetes who are receiving insulin therapy may be candidates for switching to Glimepiride Aicor®. This transition must be performed under close medical supervision.
Children.
There is insufficient data on the safety and efficacy of Glimepiride Aicor® in children; therefore, the drug is not recommended for use in this patient population.
Overdose.
Overdose may lead to hypoglycemia lasting from 12 to 72 hours, which may recur after initial improvement. Symptoms may appear up to 24 hours after drug absorption. Patients should generally be monitored in a clinical setting. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia is often accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, coordination disorders, drowsiness, coma, and seizures.
Treatment of Overdose. Treatment primarily involves preventing further drug absorption. This can be achieved by inducing vomiting, followed by ingestion of water or soda containing activated charcoal (an adsorbent) and sodium sulfate (a laxative). If a large amount of glimepiride has been ingested, gastric lavage is indicated, followed by administration of activated charcoal and sodium sulfate. In cases of severe overdose, hospitalization in an intensive care unit is required. Glucose administration should be initiated as soon as possible: if necessary, initially by a single intravenous injection of 50 mL of a 50% glucose solution, followed by infusion of a 10% glucose solution, with continuous monitoring of blood glucose levels. Further treatment is symptomatic.
When treating hypoglycemia caused by accidental ingestion of Glimepiride Aicor® in infants and young children, glucose dosage must be carefully adjusted to avoid dangerous hyperglycemia, and blood glucose levels must be closely monitored.
Adverse Reactions
Based on the experience with the drug Glimepiride Aicur® and other sulfonylurea derivatives, the following adverse reactions have been observed in clinical trials. These are listed below by organ system classes in decreasing order of frequency: very common: ≥ 1/10; common: ≥ 1/100 to <1/10; uncommon: ≥ 1/1,000 to <1/100; rare: ≥ 1/10,000 to <1/1,000; very rare: <1/10,000; frequency not known (cannot be estimated from the available data).
Blood and lymphatic system disorders.
Rare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, hemolytic anemia, and pancytopenia, which are generally reversible upon discontinuation of the drug.
Frequency not known: during post-marketing surveillance, cases of severe thrombocytopenia with platelet counts less than 10,000/µL and thrombocytopenic purpura have been reported.
Immune system disorders.
Very rare: leukocytoclastic vasculitis, moderate hypersensitivity reactions which may progress to severe forms, accompanied by dyspnea, hypotension, and sometimes shock.
Frequency not known: cross-sensitivity with sulfonamides, sulfonilureas, or related substances is possible.
Metabolism and nutrition disorders.
Rare: hypoglycemia.
Such hypoglycemic reactions usually occur immediately, may be severe, and are not always easily corrected. The occurrence of such reactions, as with treatment using other hypoglycemic agents, depends on individual factors such as dietary habits and dosage (see section "Special instructions" for details). The clinical picture of a severe hypoglycemic attack may resemble that of a stroke.
Eye disorders.
Frequency not known: transient visual disturbances may occur, particularly at the beginning of treatment, due to changes in blood glucose levels.
Gastrointestinal disorders.
Very rare: nausea, vomiting, diarrhea, sensation of fullness and discomfort in the abdomen, abdominal pain, which rarely lead to the necessity of discontinuing treatment.
Hepatobiliary disorders.
Frequency not known: increased levels of liver enzymes.
Very rare: liver function abnormalities (e.g., cholestasis or jaundice), hepatitis, and liver failure.
Skin and subcutaneous tissue disorders.
Frequency not known: allergic and pseudoallergic reactions may occur, including pruritus, rash, urticaria, and photosensitivity.
Investigations.
Very rare: decreased serum sodium levels.
Shelf life.
3 years.
Storage conditions.
Store in a place inaccessible to children. Store at a temperature not exceeding 30°C.
Packaging.
15 tablets per blister pack, 2 blisters per cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Farmaceutska-Hemijska Industrija, Zdravlje AD, Serbia.
Address of manufacturer's site of operation.
Vlajkova 199, 16000 Leskovac, Serbia.
Marketing authorization holder.
Aicur LLP.
Address of marketing authorization holder.
Suite 4073, 10 Great Russell Street, London WC1B 3BQ, United Kingdom.